Renal Flashcards
Describe the functional anatomy of the kidneys
Syllabus
Macroscopic anatomy
* Paired organ
* Blood supply - single renal artery; Venous drainage - single renal vein; Innervation - efferent strictly sympathetic T9-T12; afferent (pain) via T12
* Structural organisation: (outside to inside)
* Cortex: cortical labyrinth (glomerulus and convoluted tubules) and medullary rays(bundles of renal tubules forming in renal cortex + continue to medulla) (histological)
* Outer medulla: Outer and inner stripe
* Inner medulla: Forms tip of renal pyramids
* Minor calyces: from tips of renal pyramids & connect to major calyces
* Major calyces: join to form collecting duct
Functional anatomy
* Nephrons are the function unit of the kidneys. Each part of the nephron is made of cells specific to the function of that portion of the nephron
* Cortical nephrons
* efferent arterioles branch into peritubular capillaries (PC)
* PC are thin walled & fenestrated. They surround the PCT + DCT. Main role is reabsorption and active secretion of solutes
* Juxtamedullary
* efferent arterioles branch into vasa recta (VR)
* VR - main role is concentration of urine
* Descending VR - mainly involved in counter current mechanism; ascending VR mainly involved in reclaiming reabsorbed water from medulla
Describe renal blood flow and factors affecting it
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- 20-25% of cardiac output; with ER 10-15%. ~ 1000mL/min or 400mL/100g/min
- Consumption ~ 2mL O2/100g/min
- Most of the blood (~95%) goes to cortex, 5% goes to medulla
- ER is independent of flow
Sympathetic tone
- Vasoconstriction of efferent arterioles decreases flow
- Alpha adrenoceptor agonists will decrease renal blood flow (and slightly, filtration)
- Beta adrenoceptor agonists (juxtaglomerular cells have B1 receptors) will increase renal blood flow
Autoregulation - works on afferent arterioles. Constant blood flow over MAP 75-170mmHg
* Myogenic (50%) (onset <10s) - intrinsic to all arterioles. Stretch of arterioles results in constriction
* Tubuloglomerular feedback (35%) (onset <60s)
* Increased tubular flow in DCT –> increased Na+ uptake by macula densa cells via NKCC
* Increased [Na+] –> release of ATP/ADP/AMP (due to ATP use in Na/K ATPase at basal membrane)
* ATP/ADP/AMP –> dephosphorylation to adenosine
* Adenosine binding to A1 receptor in afferent arteriole –> large intracellular calcium influx –> vasoconstriction of afferent arteriole
Decreased flow: Reduced filtration –> lower activity of NKCC –> signalling cascade resulting in PGE2 synthesis and release. PGE2 acts on EP2 & EP4 receptors in juxtaglomerular cells and causes renin release. Renin activates RAAS leading to increased GFR
- Other mechanisms (<15%) involving angiotensin-II & NO
Humoural factors
** Vasocontrictors**
* Angiotensin II - produced systemically and locally. Constrict afferent + efferent. Decreases RBF + GFR
* Endothelin- secreted by renal endothelial cells in response to AII + shear stress. Causes profound VC of eff + aff arterioles
* Adenosine
** Vasodilator stimuli**
* Prostaglandins - increases renal blood flow without changing GFR. Dampens effect of sympathetic nerves + AII (which is important to protect against renal ischaemia)
* NO - produced by endothelium in response to many stimuli. VD eff + aff
* Bradykinin - kallikrein is produced by kidneys. This catalyses conversion of kininogen to bradykinin. BK increases GFR
* ANP/BNP*******
* High protein meal
* Hyperglycaemia
Draw the renal autoregulation graph
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Describe glomerular filtration
Syllabus
Glomerular filtration rate (GFR) is the sum of the ultrafiltrate produced by all nephrons
* ~20% of renal blood flow (RBF is 20% of cardiac output). This is called the filtration fraction
* sieving coefficient is the ratio of a molecule’s concentration in the filtrate to that in plasma
* Normal GFR = ~90-120mL/min/1.73m2
Glomerular ultrafiltration is influenced by the Starling equation:
GFR = Kf [(Pgc - PBC) - σ(πgc - πBC)]
Where:
* Kf = filtration coefficient; which is made up of:
○ k = hydrostatic permeability constant of the membrane
* Membrane permeability is in turn affected by capillary endothelium, basement membrane (negatively charged molecules have reduced filtration (BM is negatively charged)) & foot processes of podocytes (molecules < 7000 Dalton are freely filtered)
○ S = SA of the filtration surface (which can be affected by glomerular mesangial cell contraction)
* (Pgc - PBC) = hydrostatic pressure difference between glomerular capillary and Bowman’s capsule
○ Determined by RBF and relative constriction of afferent and efferent arterioles
* (πgc - πBC)= oncotic pressure difference between glomerular capillary and Bowman’s capsule
* σ = reflection coefficient for blood protein
Describe the structure and function of the renal corpuscle and PCT
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Renal corpuscle (Glomerulus and Bowman’s capsule)
* Filtration occurs through the filtration barrier of Bowman’s capsule, which is formed by 3 layers:
- Capillary endothelium - fenestrated, freely permeable to H2O, small solutes and most proteins. Have negatively charged glycoproteins - affects filtration of large anionic particles
- Basement membrane - made of negatively charged proteins
- Bowman’s capsule epithelium - covered by podocytes with extremely thin filtration slit diaphragms - size selective filtration
Proximal convoluted tubule (PCT)
* Structural anatomy
- 14mm long, with a lumen 20-30 μm in diameter
- Lined with simple cuboidal epithelium, tight junctions between cells
- Mostly in the cortex, with small straight portion in outer medulla
- Apical membrane with brush border & highly invaginated basolateral membrane with many mitochondria (increased SA +++)
* Reabsorption: 60-70% of glomerular ultrafiltrate is reabsorbed here
- Basolateral Na+/K+ ATPase activity creates sodium gradient, which drives most of the reabsorption
- Apical sodium co-transporters:
* Glucose reabsorption (SGLT2). Glucose is also reabsorbed independently via GLUT1 &2
* Phosphate reabsorption
- PCT also reabsorbs HCO3-
- Water diffuses (paracellular, transcellular via aquaporins) along with sodium, and tubular fluid remains iso-osmolar
- Albumin and protein fragments are reasbsorbed by pinocytosis
* * Secretion*:
- Apical sodium antiporters:
* Ammonia elimination
* NHE-3 proton antiporter (H+ excretion)
- Organic anion transporter (OAT-1) at peritubular capillary and OAT-4 at apical membrane facilitates secretion of:
* Organic metabolic byproducts: Urate, hippurate, creatinine
* Vitamins: folate
* Drugs: Frusemide, Metformin, Beta-lactam antibiotic, salicylates, cisplatin, tetracycline, methotrexate
- Drug targets in the proximal tubule include:
- Carbonic anhydrase –> blocked by acetazolamide
- OAT-1 –> inihibited by probenecid
Describe the structure and function of the Loop of Henle
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Loop of Henle - LoH creates an increased interstitial osmotic gradient in the medulla to allow reabsorption of H2O & production of concentrated urine ○ 20% of total water reabsorption and 25% of the total electrolyte reabsorption in the nephron happens here. - Thin descending limb - reabsorbs H2O (counter-current exchange mechanism) ○ ~10mm long. Some descend deep into the inner medulla ○ Covered in a thin simple epithelium of different cell types ○ Extremely high water permeability, poor ion permeability ○ Reabsorbs much of the filtered water (osmotic mechanism) ○ Produces concentrated tubular fluid (~1200-1400 mOsm/kg) - Thin ascending limb: ○ Extremely high ion permeability, poor water permeability ○ Reabsorbs electrolytes and urea (passive diffusion) ○ Produces highly dilute tubular fluid ( ~100 mOsm/kg) - Thick ascending limb ○ Minimal water permeability ○ Active transport of Na, K, Cl by NKCC2 § 20-30% of sodium reabsorbed § Some NH4+ is also reabsorbed by NKCC2 (resemblance to K+) § 15% of bicarb reabsorption mediated by NHE-3 and CA just like in PCT ○ Passive transport § Establishment of electrochemical gradient - Cl- reabsorption, non-reabsorption of K+ (gets recycled back to lumen by ROMK), creates positive charge in lumen, driving paracellular reabsorption of magnesium + calcium § Cl- moves out of basolateral membrane by its own channel (driven by highly negative intracellular charge)
Describe the structure and function of the DCT + collecting duct
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DCT + collecting duct - Thick ascending limb of the Loop of Henle ○ Contains juxtaglomerular apparatus. Made of: * Macula densa - sense flow rate by [Na+] concentration □ Mediates tubuloglomerular feedback (increased salt delivery results in a reflexive downregulation of glomerular blood flow) □ Mediates the secretion of renin from juxtaglomerular cells, in response to decreased salt delivery * Extraglomerular mesangial cells * Granular cells - make + store renin - Distal convoluted tubule ○ Walls thicker than thick ascending limb. Tall cuboidal cells full of mitochondria ○ Proximal DCT water impermeable ○ Defined by the expression of luminal NCC, (thiazide-sensitive Na + Cl co-transporter) * Reabsorbs 5-10% of filtered Na load. Reabsorption driven by basolateral Na+/K+ ATPase * Also contains ENaC (luminal membrane) ○ Secretes potassium to electrically balance reabsorption of sodium (source of frusemide-induced hypokalemia) * Anything that increases Na delivery to DCT will push K+ out via ROMK (voltage-dependent mechanism) ○ Essential to Mg + Ca transport - active transcellular - Connecting tubule ○ Characterised by the presence of an apical calcium transporter (TPRV5), expression regulated by PTH & 1,25-dihydroxyvitamin D3 ○ Basolateral NCX exchanger ○ Otherwise similar to the collecting duct - Collecting duct ○ Cortical (urea-impermeable) and medullary collecting duct (highly urea permeable) ○ Aldosterone increases the expression of ENaC channels * Increases Na absorption --> Increased potassium secretion (ROMK) * Drug target of spironolactone (blocks aldosterone mediated expression) and amiloride (directly blocks ENaC) ○ Vasopressin increases the expression of aquaporins (cortical duct) and UT1-3 (innermost medulla) channels * Aquaporins facilitate the reabsorption of filtered water * UT transporters - urea reabsorption (urea recycling) ○ Principle cells - NaCl reabsorption, K+ secretion, stimulated by aldosterone ○ Intercalated cells * Secrete ammonia and hydrogen ions, which combine to form ammonium in the tubule (traps H+ in lumen) * Secrete chloride to electrically balance the cationic ammonium □ Chloride reclaimed by Cl/HCO3 transporter if pH high * A breakdown of these functions leads to a Type 1 renal tubular acidosis
Explain the counter-current mechanisms in the kidney
Syllabus
The "single effect":
- The thick ascending limb of the loop of Henle extracts solutes from the tubule fluid to medullary interstitium, which becomes hyperosmolar (1200 mOsm/kg)
- H2O moves out of the thin descending limb of the loop of Henle, making the remaining fluid in the thin descending limb similarly hyperosmolar
Countercurrent multiplication of the single effect
- The movement of hyperosmolar fluid up into the thick ascending limb continuously delivers more solute which is transferred to the medullary interstitium
- The hyperosmolarity of the interstitium then extracts more water from the descending tubule fluid, maintaining its hyperosmolarity
- The concentration gradient maintained in this way reduces the energy cost of extracting solutes from the thick ascending limb.
Countercurent exchange in the vasa recta
- The vasa recta are permeable to water and solutes
- Solutes diffuse into the descending vasa recta, and then back out again as the blood returns via the ascending vasa recta
- These vessels also have slower flow because of increased cross-section ("cauda equina effect"), increasing the efficiency of solute exchange
- This mechanism prevents the washout of concentrated inner medullary solutes
- More water returns via the ascending vasa recta, removing reclaimed water from the renal medulla
Role of intrarenal urea recycling:
- Proximal cortical collecting duct is permeable to water but not to urea.
- Water can move out of the cortical collecting duct, but urea cannot, which causes the concentration of urea in the duct
- Distal collecting duct is permeable to urea --> Concentrated urea moves into the renal interstitum
- From there, it can be absorbed into the ascending limb fluid, and recycled
- Vasopressin increases the permeability of the collecting duct to urea
The osmolalities at different points in the tubule are:
Renal interstitial osmolality values:
- Cortex osmolality: 300 mOsm/kg
- Outer medulla: 800 mOsm/kg
- Inner medulla: 1200 mOsm/kg
Loop of Henle osmolality values:
- Proximal tubule, straight part: 300 mOsm/kg
- Descending limb: 800 mOsm/kg
- Hairpin turn: 1200 mOsm/kg
- Ascending thin limb: 800 mOsm/kg
- Ascending thick limb: 100 mOsm/kg, at the end
Outline the endocrine functions of the kidneys
Syllabus
RAAS system - Renin - Produced: in granular cells in the juxtaglomerular apparatus - Effects: ○ Catalyses conversion of angiotensinogen to angiotensin I in liver. Angiotensin I is converted to angiotensin II in lung by angiotensin converting enzyme (ACE) ○ Angiotensin II constricts efferent > afferent, which decreases GFR & filtered sodium load - Release is affected by: ○ Tone of afferent arteriole - a drop in afferent arteriolar tone will be detected by granular cells via stretch receptors, and result in renin secretion ○ Decreased sodium delivery to macula densa will stimulate renin release ○ Sympathetic stimulation - catecholamines bind to β1 receptors on granular cells, resulting in renin release Non RAAS hormones Erythropoietin: - Produced: in fibroblasts in renal cortex - Effects: binds EPO receptors on RBC precursors, resulting in decreased apoptosis of these cells & increased mature RBC production - Release is stimulated by: ○ Mainly by hypoxia. Angiotensin II may play a role - Release is inhibited by inflammatory cytokines Calcitriol: - Initially produced in skin (7-dehydrocholesterol is convert to cholecalciferol (vitamin D3) in presence of sunlight). This is hydroxylated in liver to 25(OH)2D3. This is converted by kidneys to active vitamin D (calcitriol) - 1-alpha,25(OH)2D3. - Site of conversion: proximal tubule - Effect: increased Ca2+ absorption from gut & DCT; increased liberation from bone - Stimuli for conversion: ○ Low serum Ca2+ , low PTH, low Vit D - Factors inhibiting conversion - calcitriol (negative feedback loop), low PTH, hypercalcaemia Others - Thrombopoietin - also produced in liver. Stimulates megakaryocytes, promoting maturation. Stimuli for release is thrombocytopenia, inhibited by platelet levels - Protaglandins - steroid hormones produced from arachadonic acid and exert their effects at the site of production ○ At renal cortex arteries/arterioles - maintain RBF & GF ○ Release stimulated by ADH, AII, NA - Kallekreins - peptide hormones produced mostly in distal nephron ○ Cleaves kininogens to bradykinin, which vasodilates afferent and efferent arterioles. Increases RBF without change in GFR, causes natriuresis + diuresis
Describe the role of bicarbonate in handling of an acid load
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Bicarbonate - Total IV bicarb ~ 24mmol/L - Renal handling ○ All filtered bicarbonate is reabsorbed by the nephron ○ 80% resorbed in PCT (linked to H+ secretion) ○ 20% resorbed in thick ascending LoH, similar mechanism to PCT (below) - Exists in equilibrium according to: CO_2+ H_2 O⇋ H_2 〖CO〗_3⇋ 〖HCO〗_3^−+ H^+ - Where H2CO3 conversion to CO2 + H2O is catalysed by carbonic anhydrase (CA) With increased acidosis (filtered H+), there will be increased production of CO2 in the tubular lumen, which is lipid soluble and diffuses into PCT cells. Here, it is converted to bicarb by cytosolic carbonic anhydrase + is transported out of the basolateral membrane by NBC-1. - The H+ that is produced by CA when bicarb is produced is recycled and excreted by NHE3
Describe the role of ammonia in the handling of an acid load by the kidneys
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Excretion of ammonium is the most important mechanism of acid excretion Ammonia/ium (responsible for 50-66%) of total daily acid-base elimination - Filtered by glomerulus - PCT - produces ammonia via Glutamine metabolism ○ Glutamine enters BL membrane via SNAT3 ○ Metabolised to NH3 by glutaminase + glutamate dehydrogenase ○ Ammonia (NH3) exists in solution with ammonium (NH4+) with pKa = 9.15, so once lipid soluble NH3 is formed and diffuses out to lumen, it immediately binds & traps H+ for excretion ○ NH4+ can also be directly pumped out by NHE3 - Ammonia/ium secretion can increase 1000-2000x throughout nephron - LoH (thick ascending limb) ○ Mimics K+ and is reabsorbed through NKCC channel ○ Becomes concentrated in the inner medulla ○ Concentrated ammonium is then secreted in the collecting duct - DCT ○ Secreted by intercalated A cells. Traps H+ here (H+ secreted by H/K ATPase + H+ ATPase) In acidosis, it would be favourable to increase the SID to normalise acidic serum pH. Therefore you want greater excretion of strong anions (eg. Cl-) --> Cl- needs to be transported with a cation, so often is transported with ammonium - In this way, ammonium further promotes normalisation of blood pH
Describe the role of titratable acids in the handling of an acid load by the kidneys
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Excretion of titratable acids: Phosphate - ~50% of titratable acids - Exists in HPO42- or H2PO4- states in tubule. - As filtered load becomes more acidic, there is a shift towards the H2PO4- (pKa = 6.8) species & less phosphate is reabsorbed, resulting in secretion (with the bound H+) Other titratable acids remove H+ by a similar mechanism - Eg. Sulfate, urate, hippurate, citrate, creatinine - These have very little effect due to low pKa or low concentration - At very low pH (<6.0), creatinine has larger effect on buffering urinary pH) Non volatile acids - Lactate, ketones, phosphate, sulfate, urate, hippurate - Freely filtered in PCT - Large fraction reabsorbed in straight portion of PCT (pars recta), and remaining fraction allows urine pH to be buffered (see ammonium + phosphate above)
Describe the renal response to respiratory and metabolic pH changes
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Renal response to acidosis and alkalosis: Regulation of bicarbonate reabsorption regulates responses to alkalosis and respiratory acid-base disturbances, but cannot compensate for metabolic acidosis, as the maximum effect is a maintenance of the status quo (when 100% of bicarbonate is reabsorbed) Response to respiratory acidosis: - For every 10mmHg rise in CO2, bicarbonate level will rise by 4mmol/L - Mechanism: ○ Increasing amounts of CO2 in blood will result in increasing diffusion into tubular cells down concentration gradient (diffuses easily through lipid bilayer) ○ Increasing conversion of CO2 to HCO3 in PCT by carbonic anhydrase + H+ excretion via NHE3 and H+ pumps Response to respiratory alkalosis: - Essentially opposite - decreased secretion of titratable acids, decreased bicarb reabsorption Response to metabolic acidosis: - Increased uptake of glutamine by tubular cells ○ Glutamine deaminated twice to give 2x ammonia molecules + § Ammonia is secreted into tubule + traps H+ ion § α-ketoglutarate is converted to glucose and enters CAC --> CO2 + H2O produced § Overall glutamine uptake results in removal of H+ and new HCO3- formation. Opposite will happen for metabolic alkalosis
Describe the changes in urinary pH along the nephron
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